Effects of endogenous hypercortisolism on bone mRNA and microRNA expression in humans

Abstract

An excess of endogenous GC in humans suppresses bone formation through the upregulation of Wnt-signaling antagonists and dysregulation of miRs involved in mesenchymal stem-cell commitment. Both Wnt-signaling antagonists and miRs seem to be promising targets for further research in therapeutic intervention in glucocorticoid-induced osteoporosis.

Active Cushing syndrome patients have increased ectopic fat deposition and bone marrow fat content compared to cured patients and healthy subjects: a pilot 1H-MRS study

“…Peroxisome proliferator-activated receptor-gamma (PPAR-γ), which represses osteogenic transcription factors (runt-related transcription factor 2 and osterix) and stimulates expression of adipogenic genes in bone marrow, was already found to be modulated by hypercortisolism in VAT (28). Glucocorticoids can also dysregulate Wnt/β catenin signaling, which is a key regulator of the two lineages, by stimulating Wnt antagonists (sclerostin and dickkopf-1), as shown in studies conducted in humans and mice (29,30,31).…”

Extracellular Vesicle microRNAs Contribute to the Osteogenic Inhibition of Mesenchymal Stem Cells in Multiple Myeloma

“…Among the 384 microRNAs contained in the card, we identified 164 miRNAs in EVs from the MM1.S cell line and we then selected the most enriched ones based on their expression level (Ct <31, 2ˆ∆Ct ≥0.002). Out of forty enriched miRNAs, seven of them have been previously correlated with osteogenesis regulation (hsa-miR-34a [35][36][37], hsa-miR-30c [26,38], hsa-miR-127-5p [39,40], hsa-miR-106a [41], hsa-miR-188-3p [37], hsa-miR-129-5p [42][43][44][45], hsa-miR-146a [46,47] (Figure 2) Among those, we decided to focus our attention on hsa-miR-30c, hsa-miR-127-5p, hsa-miR-129-5p, and hsa-miR-146a since their validated and predicted targets are osteoblast differentiation markers. The presence of the four selected miRNAs in MM EVs was further confirmed by qRT-PCR in MM1.S and RPMI 8226 EVs as well as in the respective producing cell lines ( Figure 3A).…”

The role of microRNAs in glucocorticoid action

“…However, the general consequences of a global inhibition of miRNA production are unclear, due to the broad roles of miRNAs and the varied context-specific effects of GCs. The proposed mechanism of miRNA inhibition is also inconsistent with the multiple reports of GC-induced miRNA up-regulation in multiple cell types (67,80,95,96) and the observations of transcriptional inhibition, for example of the miR-17ϳ92 cluster (79). These studies do, however, highlight the many potential mechanisms by which GCs can alter miRNA abundance, either in a miRNA-specific manner or more broadly.…”